Please wait a minute...

中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志  2019, Vol. 39 Issue (2): 49-61    DOI: 10.13523/j.cb.20190207
精准医疗与伴随诊断专刊     
TAEST16001:TCR亲和力增强型特异性T细胞免疫治疗
区裕升,郑红俊,钟时,李懿()
广东香雪精准医疗技术有限公司 广州 510663
TAEST16001:TCR Affinity Enhanced Specific-T-cell Therapy
Yu-sheng OU,Hong-jun ZHENG,Shi ZHONG,Yi LI()
Guangdong Xiangxue Life Sciences Ltd. Guangzhou 510663, China
 全文: PDF(562 KB)   HTML
摘要:

人体的免疫系统, 相比于二十年前,通过近几十年的研究积累已经被比较清晰地诠释。特别是其在肿瘤的发生发展中的作用已引起前所未有的重视。人们发现利用免疫系统的相关分子可以非常有效地控制癌症,甚至可以完全治愈癌症。在一开始,这种现象仅是比较零星地在专业圈子里流传,但自从癌症的免疫治疗于2013年被Science杂志评为年度十大科技突破之首后,免疫治疗的成果便不断刷屏普通人的信息网络。这一现象的高潮表现在2018年诺奖评委再也按耐不住原本谨慎的态度,终于将医学与生理学奖颁发给了两位免疫学家,以表彰他们分别发现两个重要的免疫调控分子PD-1和CTLA-4的作用。因为靶向这两个分子的抗体在肿瘤的免疫治疗中表现出可预测的效果。更进一步的肯定是将同年的诺贝尔化学奖的一半授予了产生抗体的噬菌体展示技术的发明者。因此免疫治疗成为肿瘤治疗的重要手段,被列为继手术、放疗、化疗之后的第四种模式,就变成不争的事实了。肿瘤免疫治疗可以通过单一分子药物来实现,也可以通过含有成千上万分子的免疫细胞来完成。而后者则是借助细胞工程技术,修饰相关的免疫细胞,在体外扩增后回输给相应的患者,以增强和激发机体的抗肿瘤免疫能力,并最终达到清除体内肿瘤细胞的目的。对T细胞免疫治疗的相关原理及目前应用发展情况进行了简单的介绍,并且对香雪集团旗下控股子公司广东香雪精准医疗技术有限公司的第一款临床研究阶段产品TAEST16001的特性及相关伴随诊断试剂盒的研发进行了简单的描述。

关键词: 免疫细胞治疗T细胞受体工程化的T细胞软组织肉瘤嵌合抗原受体T细胞    
Abstract:

The illustration of human immune system has been substantially clearer than 20 years ago with the credit of a vast amount of comprehensive studies for decades. In particular, its role in tumor development has attracted unprecedented attention. It has been found that the molecules of the immune system can be utilized very effectively to control cancer development and even cure cancer completely. At the early days, this phenomenon was only sporadically spread in professional circles, but since cancer immunotherapy became the winner of Science’s top ten breakthroughs of the year in 2013, publics have been constantly refreshed by the results of immunotherapy. The climax of this phenomenon is reflected in the 2018 Nobel Prize judges who were unable to hold on their usual cautious and awarded the Medical and Physiology Award to two immunologists in recognition of their discovery of the regulatory mechanism of two important immune molecules, PD-1 and CTLA-4, since antibodies targeting these two molecules show predictable effects in tumor immunotherapy. A further affirmation is that half of the Nobel Prize in Chemistry of the same year was awarded to the inventors of phage-display technology for generation of antibodies. Therefore, immunotherapy has become an important approach of cancer treatment, and it has become an indisputable fact that it is listed as the fourth treatment mode after surgery, radiotherapy and chemotherapy. Tumor immunotherapy can be achieved by biologics or by immune cells. The latter is to modify and expand the relevant immune cells by cell engineering technology, and then infuse the cells to the corresponding patients to enhance the patient’s anti-tumor immunity, and ultimately achieve the purpose of eliminating tumor cells. In this paper, the concepts of T-cell immunotherapy and the current development of its application are briefly described. In addition, the first clinic stage product TAEST16001 and the companion diagnostic kits of Guangdong Xiangxue Life Sciences Ltd., a subsidiary of Xiangxue Group, has been briefly presented.

Key words: Immune cell therapy    T cell receptor engineered T-Cell (TCR-T)    Soft tissue sarcoma    Chimeric antigen receptor T-Cell (CAR-T)    Companion diagnostic
收稿日期: 2019-01-10 出版日期: 2019-03-26
ZTFLH:  Q819  
服务  
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章  
区裕升
郑红俊
钟时
李懿

引用本文:

区裕升,郑红俊,钟时,李懿. TAEST16001:TCR亲和力增强型特异性T细胞免疫治疗[J]. 中国生物工程杂志, 2019, 39(2): 49-61.

Yu-sheng OU,Hong-jun ZHENG,Shi ZHONG,Yi LI. TAEST16001:TCR Affinity Enhanced Specific-T-cell Therapy. China Biotechnology, 2019, 39(2): 49-61.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20190207        https://manu60.magtech.com.cn/biotech/CN/Y2019/V39/I2/49

第一代TCR-T 第二代TCR-T 第三代TCR-T
操作方法 从肿瘤组织中分离出浸润性淋巴细胞或自体T细胞群中分离出特定的识别某种抗原的 T 细胞寡克隆,体外扩增后回输给病人 分离识别某种抗原的 T 细胞单克隆,获得野生型 TCR 基因序列,转导至病人的 T 细胞 将获得的野生型 TCR 进行亲和力优化,转导亲和力增强的TCR 到病人的 T 细胞
特点 自体肿瘤抗原特异性 T 细胞数量极少,难以产业化
野生型 TCR 亲和力低,导致杀伤肿瘤的效果有限
野生型 TCR 亲和力低,导致杀伤肿瘤的效果有限 对抗肿瘤的免疫逃逸,提高其成药性
国外研究情况 NIH/Steve Rosenberg
Cassian Yee
NIH/Steve Rosenberg
LTCR-H1
Adaptimmune
Carl June
Steve Rosenberg
表1  比较三代TCR-T平台特点
伴随诊断试剂盒 适应症 商品名(通用名)
BRACAnalysis CDx 乳腺癌 利普卓 (奥拉帕尼)
Talzenna(他拉唑帕尼)
卵巢癌 利普卓(奥拉帕尼)
Rubraca(芦卡帕利)
therascreen EGFR RGQ PCR Kit 非小细胞性肺癌 易瑞沙(吉非替尼)
Gilotrif (阿法替尼)
Vizimpro(达克替尼)
cobas EGFR Mutation Test v2 非小细胞性肺癌 (组织和血浆) 特罗凯(厄洛替尼)
泰瑞沙(奥希替尼)
易瑞沙(吉非替尼)
PD-L1 IHC 22C3 pharmDx 非小细胞性肺癌, 胃或胃食管交界处腺癌, 宫颈癌, 尿路上皮癌 可瑞达 (帕博利珠单抗)
PD-L1 (SP142) 非小细胞性肺癌, 尿路上皮癌 Tecentriq (阿特珠单抗)
Abbott RealTime IDH1 急性髓性白血病 Tibsovo (ivosidenib)
MRDx BCR-ABL Test 慢性骨髓白血病 Tasigna (尼洛替尼)
FoundationOne CDx 非小细胞性肺癌 Gilotrif (阿法替尼)
易瑞沙(吉非替尼)
特罗凯(厄洛替尼)
泰瑞沙(奥希替尼)
Alecensa (阿雷替尼)
赛可瑞 (克唑替尼)
Zykadia (色瑞替尼)
Tafinlar (达拉非尼) 与Mekinist (曲美替尼) 联合用药
黑色素瘤 Tafinlar (达拉非尼)
Zelboraf (威罗菲尼)
Mekinist (曲美替尼)或Cotellic (考比替尼)与Zelboraf (威罗菲尼) 联合用药
表2  已上市带有伴随诊断的药物及其关联使用[34]
伴随诊断试剂盒 适应症 商品名(通用名)
乳腺癌 赫赛汀 (曲妥珠单抗)
Perjeta (帕妥珠单抗)
Kadcyla (曲妥珠单抗 抗体-药物偶联物) - BLA 125427
结肠直肠癌 爱必妥 (西妥昔单抗)
维克替比 (帕尼单抗)
卵巢癌 Rubraca(芦卡帕利)
VENTANA ALK (D5F3) CDx Assay 非小细胞性肺癌 Zykadia (色瑞替尼)
赛可瑞 (克唑替尼)
Alecensa (阿雷替尼)
Abbott RealTime IDH2 急性髓性白血病 Idhifa (恩西地平)
Praxis Extended RAS Panel 结肠直肠癌 维克替比 (帕尼单抗)
Oncomine Dx Target Test 非小细胞性肺癌 Tafinlar (达拉非尼)
Mekinist (曲美替尼)
赛可瑞 (克唑替尼)
易瑞沙(吉非替尼)
LeukoStrat CDx FLT3 Mutation Assay 急性骨髓性白血病 Rydapt (米哚妥林)
Xospata (吉特替尼)
FoundationFocus CDxBRCA Assay 卵巢癌 Rubraca(芦卡帕利)
Vysis CLL FISH Probe Kit 慢性骨髓细胞性白血病 Venclexta (维奈妥拉)
KIT D816V Mutation Detection by PCR for Gleevec Eligibility in Aggressive Systemic Mastocytosis (ASM) 系统性肥大细胞增多症 格列卫 (甲磺酸伊马替尼)
PDGFRB FISH for Gleevec Eligibility in Myelodysplastic Syndrome / Myeloproliferative Disease (MDS/MPD) 骨髓发育异常综合征/骨髓增殖性疾病 格列卫 (甲磺酸伊马替尼)
cobas KRAS Mutation Test 结肠直肠癌 爱必妥 (西妥昔单抗)
维克替比 (帕尼单抗)
therascreen KRAS RGQ PCR Kit 结肠直肠癌 爱必妥 (西妥昔单抗)
维克替比 (帕尼单抗)
Dako EGFR pharmDx Kit 结肠直肠癌 爱必妥 (西妥昔单抗)
维克替比 (帕尼单抗)
FerriScan 非输血依赖性地中海贫血 Exjade (地拉罗斯)
Dako c-KIT pharmDx 胃肠道间质瘤 格列卫 (甲磺酸伊马替尼)
INFORM HER-2/neu 乳腺癌 赫赛汀 (曲妥珠单抗)
PathVysion HER-2 DNA Probe Kit 乳腺癌 赫赛汀 (曲妥珠单抗)
PATHWAY anti-Her2/neu (4B5) Rabbit Monoclonal Primary Antibody 乳腺癌 赫赛汀 (曲妥珠单抗)
InSite Her-2/neu KIT 乳腺癌 赫赛汀 (曲妥珠单抗)
SPOT-LIGHT HER2 CISH Kit 乳腺癌 赫赛汀 (曲妥珠单抗)
Bond Oracle HER2 IHC System 乳腺癌 赫赛汀 (曲妥珠单抗)
HER2 CISH pharmDx Kit 乳腺癌 赫赛汀 (曲妥珠单抗)
表2-1  (续)
伴随诊断试剂盒 适应症 商品名(通用名)
INFORM HER2 Dual ISH DNA Probe Cocktail 乳腺癌 赫赛汀 (曲妥珠单抗)
HercepTest 乳腺癌 赫赛汀 (曲妥珠单抗)
Perjeta (帕妥珠单抗)
Kadcyla (曲妥珠单抗 抗体-药物偶联物)
胃和胃食管癌 赫赛汀 (曲妥珠单抗)
HER2 FISH pharmDx Kit 乳腺癌 赫赛汀 (曲妥珠单抗)
Perjeta (帕妥珠单抗)
Kadcyla (曲妥珠单抗 抗体-药物偶联物)
胃和胃食管癌 赫赛汀 (曲妥珠单抗)
THXID BRAF Kit 黑色素瘤 Braftovi (康奈非尼) 与Mektovi (binimetinib)联合用药
Mekinist (曲美替尼)
Tafinlar (达拉非尼)
Vysis ALK Break Apart FISH Probe Kit 非小细胞性肺癌 赛可瑞 (克唑替尼)
cobas 4800 BRAF V600 Mutation Test 黑色素瘤 Zelboraf (威罗菲尼)
Cotellic (考比替尼) 与Zelboraf (威罗菲尼)联合用药
表2-2  (续)
[1] Robbins P F, El-Gamil M, Li Y F , et al. Multiple HLA class II-restricted melanocyte differentiation antigens are recognized by tumor-infiltrating lymphocytes from a patient with melanoma. The Journal of Immunology, 2002,169(10):6036-6047.
doi: 10.4049/jimmunol.169.10.6036 pmid: 12421991
[2] Fesnak A D, June C H, Levine B L . Engineered T cells: the promise and challenges of cancer immunotherapy. Nature Reviews. Cancer, 2016,16(9):566-581.
doi: 10.1038/nrc.2016.97 pmid: 27550819
[3] Van Schandevyl S, Kerre T . Chimeric antigen receptor T-cell therapy: design improvements and therapeutic strategies in cancer treatment. Acta Clinica Belgica, 2018: 1-7.
doi: 10.1080/17843286.2018.1545373
[4] Tammana S, Huang X, Wong M , et al. 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. Human Gene Therapy, 2010,21(1):75-86.
doi: 10.1089/hum.2009.122 pmid: 19719389
[5] Zhang H, Snyder K M, Suhoski M M , et al. 4-1BB is superior to CD28 costimulation for generating CD8+ cytotoxic lymphocytes for adoptive immunotherapy. Journal of Immunology, 2007,179(7):4910-4918.
doi: 10.4049/jimmunol.179.7.4910 pmid: 17878391
[6] Morgan R A, Yang J C, Kitano M , et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular Therapy, 2010,18(4):843-851.
doi: 10.1038/mt.2010.24 pmid: 20179677
[7] Rosenberg S A, Kochenderfer J N . Personalized cell transfer immunotherapy for B-cell malignancies and solid cancers. Molecular Therapy: The Journal of the American Society of Gene Therapy, 2011,19(11):1928-1930.
doi: 10.1038/mt.2011.223 pmid: 22051601
[8] Porter D L, Levine B L, Kalos M , et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. New England Journal of Medicine, 2011,365(8):725-733.
doi: 10.1056/NEJMoa1103849
[9] Mueller K T, Maude S L, Porter D L , et al. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood, 2017,130(21):2317-2325.
doi: 10.1182/blood-2017-06-786129 pmid: 28935694
[10] Morgan R A, Dudley M E, Wunderlich J R , et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 2006,314(5796):126-129.
doi: 10.1126/science.1129003
[11] Holler P D, Holman P O, Shusta E V , et al. In vitro evolution of a T cell receptor with high affinity for peptide/MHC. Proceedings of the National Academy of Sciences of the United States of America, 2000,97(10):5387-5392.
doi: 10.1073/pnas.080078297 pmid: 10779548
[12] Tan M P, Gerry A B, Brewer J E , et al. T cell receptor binding affinity governs the functional profile of cancer-specific CD8+ T cells. Clinical and Experimental Immunology, 2015,180(2):255-270.
doi: 10.1111/cei.12570
[13] Zhong S, Malecek K, Johnson L A , et al. T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proceedings of the National Academy of Sciences of the United States of America, 2013,110(17):6973-6978.
doi: 10.1073/pnas.1221609110 pmid: 23576742
[14] Hay K A . Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy. British Journal of Haematology, 2018,183(3):364-374.
doi: 10.1111/bjh.2018.183.issue-3
[15] Xu J, Wang Q, Xu H , et al. Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma. Journal of Hematology & Oncology, 2018,11(1):128.
doi: 10.1186/s13045-018-0672-7
[16] Shalabi H, Wolters P L, Martin S , et al. Systematic evaluation of neurotoxicity in children and young adults undergoing CD22 chimeric antigen receptor T-Cell therapy. Journal of Immunotherapy, 2018,41(7):350-358.
doi: 10.1097/CJI.0000000000000241 pmid: 30048343
[17] Stauss H J, Morris E C, Abken H . Cancer gene therapy with T cell receptors and chimeric antigen receptors. Current Opinion in Pharmacology, 2015,24:113-118.
doi: 10.1016/j.coph.2015.08.006 pmid: 26342910
[18] Hunder N N, Wallen H, Cao J , et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. The New England Journal of Medicine, 2008,358(25):2698-2703.
doi: 10.1056/NEJMoa0800251
[19] Johnson L A, Morgan R A, Dudley M E , et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood, 2009,114(3):535-546.
doi: 10.1182/blood-2009-03-211714 pmid: 19451549
[20] Robbins P F, Morgan R A, Feldman S A , et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. Journal of Clinical Oncology, 2011,29(7):917-924.
doi: 10.1200/JCO.2010.32.2537 pmid: 21282551
[21] Robbins P F, Kassim S H , Tran T L N, et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clinical Cancer Research, 2015,21(5):1019-1027.
doi: 10.1158/1078-0432.CCR-14-2708
[22] Rapoport A P, Stadtmauer E A , Binder-Scholl G K, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nature Medicine, 2015,21(8):914-921.
doi: 10.1038/nm.3910 pmid: 26193344
[23] Li Y, Moysey R, Molloy P E, Vuidepot A-L , et al. Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nature Biotechnology, 2005,23(3):349-354.
doi: 10.1038/nbt1070 pmid: 15723046
[24] Krishnadas D K, Bai F, Lucas K G . Cancer testis antigen and immunotherapy. Immuno Targets and Therapy, 2013,2:11-19.
doi: 10.2147/ITT.S35570 pmid: 27471684
[25] Sarcoma Committee of China Anti-Cancer Association, Chinese Society of Clinical Oncology. Chinese expert consensus on diagnosis and treatment of soft tissue sarcomas Version 2015. Chinese Journal of Oncology, 2016,38(4):310-320.
doi: 10.3760/cma.j.issn.0253-3766.2016.04.013 pmid: 27087380
[26] Yang L, Fang Z W, Fan Z F , et al. An analysis of incidence trends and characteristics of soft tissue sarcoma in Beijing, 1999-2013. Chinese Journal of Oncology, 2017,39(6):471-476.
doi: 10.3760/cma.j.issn.0253-3766.2017.06.013 pmid: 28635239
[27] J?rgensen J T . The importance of predictive biomarkers in oncology drug development. Expert Review of Molecular Diagnostics, 2016,16(8):807-809.
doi: 10.1080/14737159.2016.1199962 pmid: 27282189
[28] Papadopoulos N, Kinzler K W, Vogelstein B . The role of companion diagnostics in the development and use of mutation-targeted cancer therapies. Nature Biotechnology, 2006,24(8):985-995.
doi: 10.1038/nbt1234 pmid: 16900147
[29] Roscoe D M, Hu Y-F, Philip R . Companion diagnostics: a regulatory perspective from the last 5 years of molecular companion diagnostic approvals. Expert Review of Molecular Diagnostics, 2015,15(7):869-880.
doi: 10.1586/14737159.2015.1045490 pmid: 26109316
[30] Nagai S, Urata M, Sato H , et al. Evolving Japanese regulations on companion diagnostics. Nature Biotechnology, 2016,34:141-144.
doi: 10.1038/nbt.3478 pmid: 26849515
[31] Enzmann H, Meyer R, Broich K . The new EU regulation on in vitro diagnostics: potential issues at the interface of medicines and companion diagnostics. Biomarkers in Medicine, 2016,10(12):1261-1268.
doi: 10.2217/bmm-2016-0233 pmid: 27661101
[32] J?rgensen J T, Hersom M . Companion diagnostics-a tool to improve pharmacotherapy. Annals of Translational Medicine, 2016,4(24):482.
doi: 10.21037/atm.2016.12.26 pmid: 28149844
[33] J?rgensen J T, Winther H. The development of the HercepTest - from bench to bedside//Molecular Diagnostics-The Key Driver of Personalized Cancer Medicine. Singapore: Pan Stanford Publishing Pte. Ltd., 2010: 43-60.
[34] FDA. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). [2019-01-04]..
[1] 王跃,王恒哲,毛开云,范月蕾,江洪波. 全球免疫细胞治疗药物开发现状与趋势 *[J]. 中国生物工程杂志, 2018, 38(10): 90-102.